Zeissig Lab

More information: https://tu-dresden.de/cmcb/crtd/forschungsgruppen/crtd-forschungsgruppen/zeissig

Research focus

Immunological mechanisms of inflammation and cancer (Group leader: Prof. Sebastian Zeissig, MD)

Research in the laboratory focuses on the immunological mechanisms of inflammation and tumor development in the intestine and the liver, with particular interest in translational research focusing on monogenic forms of inflammatory bowel disease and the role of inflammation in cancer development.

Microbiota, Inflammation, and Cancer

 Chronic inflammation is a risk factor for the development of cancer and many prominent examples of this association exist in the gastrointestinal tract. This includes associations between inflammatory bowel disease (IBD) and colorectal cancer (CRC), Helicobacter pylori infection and gastric cancer, Hepatitis B and C virus infections and hepatocellular cancer (HCC) as well as non-alcoholic fatty liver disease and HCC. Of note, in many of these examples, inflammation is clinically inapparent, restricted to the respective tissue and dependent on microbial organisms. In line with the principles, we could recently demonstrate that not only sporadic CRCs but also adenomas as their benign predecessor lesions are associated with disruption of the intestinal barrier and translocation of bacteria into host tissue (Peuker,…,Zeissig, Nat. Med. 2016). This is associated with the activation of inflammatory pathways in the intestinal epithelium, such as the pathway of calcineurin and nuclear factor of activated T cells (NFAT), which promotes tumor growth through support of tumor stem cell survival and proliferation. The observation that such pathways are activated early in the process of tumor development suggests that targeting of microbial elements or downstream molecular mediators may provide efficacy in the prevention of tumor development, which is currently being investigated in the lab. Moreover, we explore whether similar pathways are active in other diseases associated with barrier dysfunction, such as liver cirrhosis, and similarly promote tumor development in these organs.

Monogenetic forms of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic intestinal inflammation. In the vast
majority of IBD patients, intestinal inflammation occurs through a complex and incompletely understood interplay of genetic and environmental factors. However, we and others have recently identified forms of mono- or oligogenic forms of IBD, in which one or few genetic defects are sufficient to promote intestinal inflammation (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). Patients with monogenic IBD often present with early-onset disease manifesting during early childhood and exhibit severe and often treatment-refractory intestinal and systemic inflammation. The identification of a genetic etiology in some of these IBD patients not only provided significant insight into the pathophysiology of IBD, but also opened new opportunities for personalized treatment of these patients. This translational research agenda is pursued in close collaboration with the Department of Pediatrics (Prof. Dr. Berner, Prof. Dr. Schütz, Dr. Y.Zeißig) and the Institute of Clinical Molecular Biology (IKMB) Kiel (Prof. Dr. Schreiber, Prof. Dr.
Franke). Genetic screening is offered to patients with early onset and/or familial IBD.

Lipid Antigens in immunity

Natural killer T (NKT) cells are an unconventional subset of T cells that responds to CD1d-restricted presentation of self and foreign lipid antigens and is associated with immediate innate-like effects on NK, T, and B cells thereby shaping and orchestrating immune responses. NKT cells are critical for antimicrobial immunity and genetic defects in lipid antigen presentation are associated with primary immunodeficiency in humans. However, recent studies have revealed that NKT cells are not only contributing to protective immunity but also play central roles in the pathogenesis of chronic inflammatory disorders. Thus, it was shown that ulcerative colitis, an inflammatory bowel disease (IBD), is characterized by NKT cell-dependent intestinal inflammation. Similarly, recent studies have revealed that NKT cells are centrally involved in the pathogenesis of autoimmune and infectious hepatitis.

In our recent work investigating the role of lipid antigens and NKT cells in intestinal and hepatic immunity, we could demonstrate that hepatocytes and intestinal epithelial cells can present lipid antigens via the non-classical MHC class I molecule CD1d to natural killer T cells thus providing the basis for protection from infectious hepatitis as well as intestinal inflammation (Zeissig et al., Nat. Med. 2012; Olszak et al., Nature 2014). Furthermore, this work revealed an essential role of the commensal microbiota and microbiota-derived lipid antigens in the control of homeostasis at mucosal surfaces and demonstrated that primary defects in lipid antigen presentation are associated with immunodeficiency in humans (An et al., Cell 2014; Olszak et al., Science 2012; Zeissig et al., J. Clin. Invest.; Zeissig et al., Nat. Immunol. 2014). Current work in the laboratory is focused on the identification of lipid antigens which link metabolism and immunity in the liver and the intestine (Melum et al., Nat. Immunol. 2019).

Team

Publications

https://www.ncbi.nlm.nih.gov/pubmed/?term=zeissig-s+not+zeissig-sr